Heart failure due to myocardial infarction (MI) is leading cause of death in the United States. Infiltration of peripheral monocytes and resident cardiac macrophages are postulated to play a dual role in the post-MI period, characterized by pro-inflammatory signaling and phagocytic removal of dead cells in the early phase and a shift towards anti-inflammatory signaling to promote reparative phase. Persistence of pro-inflammatory macrophages correlates with maladaptive left ventricular remodeling and progressive heart failure. Obesity and resultant (type II) diabetes have reached epidemic proportions and predispose to development of heart failure by provoking development of lipid overload in myocardium, i.e. cardiac lipotoxicity; and by promoting coronary artery disease in concert with other risk factors such as hypertension, hyperlipidemia and a sedentary lifestyle. Early macrophage recruitment drives inflammation and promotes development of lipotoxic cardiomyopathy in animal models. These observations indicate that strategies to modulate macrophage inflammatory phenotype may be of therapeutic benefit. Emerging data point to a critical role for lysosomal function in macrophage inflammatory responses. TFEB and TFE3, two closely related family members have been demonstrated to function as the master transcriptional activators of the lysosomal biogenesis program in macrophages, acting in a mutually redundant fashion; and activation of TFEB and TFE3 is essential for sustaining macrophage phagocytosis. Our preliminary and published findings demonstrate that macrophage TFEB expression attenuates post-MI remodeling and protects against lipotoxic cell death. We have previously found that intermittent fasting activates TFEB to stimulate lysosome function in the myocardium and attenuate cardiac myocyte death during MI. Our preliminary data demonstrate that intermittent fasting rescues mortality and attenuates the inflammatory response to prevent cardiomyopathy and heart failure in MHC-ACSL1 mice with cardiac lipotoxicity due to transgenic expression of acylCoA-synthetase 1 (ACSL1); suggesting that intermittent fasting may also modulate macrophage lysosome function and the inflammatory response. In this proposal, we hypothesize that TFEB/TFE3-mediated transcriptional regulation of the macrophage lysosome biogenesis program is critical to attenuate inflammatory responses in the myocardium, post-MI and under lipotoxic stress; and can be harnessed therapeutically to prevent heart failure. In aim 1, we will examine the role of the macrophage lysosome biogenesis program in preventing post-MI heart failure in a closed chest model of cardiac ischemia-reperfusion injury and attenuating cardiomyopathy secondary to lipotoxicity in the MHC-ACS mouse model. In aim 2, we will examine the mechanisms for TFEB/TFE3-mediated modulation of macrophage phenotype. In aim 3, we will evaluate the efficacy of trehalose, an activator of TFEB/TFE3-induced lysosomal biogenesis, in attenuating the macrophage inflammatory response and cardiomyopathy, post-MI and under lipotoxic stress. These studies will identify TFEB/TFE3-transcriptional program as a potential therapeutic target to modulate cardiac macrophage function in post-MI heart failure and lipotoxic cardiomyopathy. Administration of trehalose, a naturally occurring and safe compound, has tremendous potential as a therapy to activate this pathway for prevention and/or treatment of cardiomyopathy and heart failure.